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Abstract: Most of our current understanding of the genetic predisposition to autoimmune disease can be traced to experiments performed in the decade from 1971 to 1981. Chella David was a key contributor to this research. Many of these early steps came from studies of experimental autoimmune thyroiditis. This model has been especially valuable because essentially the same disease can occur spontaneously in selected strains of animals or can be induced by deliberate immunization. From a genetic point of view, the disease has been investigated in three different species: mice, rats and chickens. The same antigen, thyroglobulin, initiates the disease in all three species. Among the main discoveries were the relationship of autoimmune disease to the major histocompatibility complex (MHC), the interplay of different subregions within the MHC in promoting or retarding development of disease, the differing roles of MHC class II and MHC I class genes in induction and effector phases, respectively, and the cumulative effect of non-MHC genes, each of which represents a small addition to overall susceptibility. Other experiments revealed that genetic differences in thyroglobulin allotypes influence susceptibility to thyroiditis. Thyroid glands differed in different strains in vulnerability to passive transfer of antibody. The first evidence of modulatory genes on the sex-related X chromosome emerged. All of these genetic findings were concurrently translated to the human disease, Hashimoto’s thyroiditis, where thyroglobulin is also the initiating antigen. [Copyright &y& Elsevier]

Abstract: Autoimmune thyroiditis, also known as chronic lymphocytic or Hashimoto''s thyroiditis, is characterized by infiltration of the thyroid gland by inflammatory cells and production of autoantibodies to thyroid-specific antigens thyroglobulin and thyroperoxidase. It is accompanied by hypothyroidism due to destruction and eventual fibrous replacement of the follicle cells. Autoimmune thyroiditis is clearly multifactorial in etiology with genetic and environmental factors contributions. Excess dietary Iodine can exacerbate thyroiditis in genetically susceptible hosts such as the NOD.H2h4 mouse. In this mouse excess dietary iodine leads to an increased immunogenicity of the thyroglobulin molecule and enhanced expression of ICAM-1 on thyroidal follicle cells. We present evidence here that ICAM-1 expression is enhanced by the elevated generation of reactive oxygen species (ROS). The anti-oxidant diphenyleneiodium (DPI), an inhibitor of NADPH oxidase, reduced both the generation of ROS and of ICAM-1 expression in cultures of NOD.H2h4 mouse thyrocytes. These results suggest that antioxidants may have therapeutic value in preventing autoimmune thyroiditis. [Copyright &y& Elsevier]

Mononuclear cell infiltration of the thyroid gland is a common histologic feature of chronic lymphocytic thyroiditis. Although the infiltrating mononuclear cells have been implicated in the destruction of the thyroid, information concerning the progression of infiltration into the thyroid is limited. In this report, we examine the composition and kinetics of mononuclear cell infiltration in the thyroid and the expression of major histocompatibility complex class II (I-Ak), IL-12, and IFN-γ in the thyroid of the NOD-H2h4 mouse, a model of spontaneous autoimmune thyroiditis accelerated by the administration of excess dietary iodine. Mice were given a low dose of 0.015% NaI in their drinking water for 2, 4, 6, 8, and 16 weeks, and thyroids were removed, serially sectioned, and stained in an avidin-biotin peroxidase assay. The thyroid infiltrate included CD4+ and CD8+ T cells, F4/80+ macrophages, and B220+ B cells. After 2 weeks of iodine treatment, CD4+ T cells were the first seen in the thyroid, followed by CD8+ T cells and F4/80+ macrophages. B220+ B cells entered the thyroid after 4 weeks of iodine treatment. IL-12 and IFN-γ positive cells were located in the thyroid early in disease and were up-regulated in the focal accumulations of infiltrating cells. Thyrocytes clearly expressed I-Ak after 4 weeks of iodine treatment near the location of mononuclear cell infiltration. [Copyright &y& Elsevier]

Mononuclear cell infiltration of the thyroid is a prominent feature of chronic lymphocytic thyroiditis. Adhesion molecules play a major role in determining the localization of inflammatory mononuclear cells in the thyroid. Previous reports from animal models and human studies have described the thyroidal expression of adhesion molecules only late in clinical disease. In this study, we examined the distribution and kinetics of expression of E-selectin, VCAM-1, LFA-1, and ICAM-1 in the NOD-H2h4 mouse, a model of spontaneous autoimmune thyroiditis accelerated by dietary iodine. Mice were fed 0.015% NaI in their drinking water for 2, 4, 6, 8, and 16 weeks, and thyroids were removed, serially sectioned, and stained in an avidin–biotin–peroxidase assay. We found a dramatic increase in E-selectin and VCAM-1 expression on intrathyroidal endothelial cells after 16 weeks of iodine treatment. In addition, we describe for the first time that thyrocytes from the NOD-H2h4 mouse, and the parental NOD, constitutively express ICAM-1 independent of iodine treatment and prior to mononuclear cell infiltration of the thyroid gland. ICAM-1 was not detected on the thyrocytes of other untreated strains of mice, implicating expression of this adhesion molecule as a critical event in the recruitment of inflammatory mononuclear cells to the thyroid. [Copyright &y& Elsevier]

The genetic control of the levels of autoantibodies has rarely been examined. We examined the heritability of autoantibodies to glutamic acid decarboxylase (GAD65) in type 1 diabetes, and to thyroglobulin (Tg) in chronic lymphocytic thyroiditis and thyrotoxicosis, using regression of offspring on midparent (ROMP) methods. Levels of autoantibodies in patients and their parents were significantly correlated in thyrotoxicosis (R² = 0.569, p = 0.001), consistent with the reported Gm association, but not in chronic lymphocytic thyroiditis or type 1 diabetes. Extension of the procedure to other autoantibody disorders could be informative. [ABSTRACT FROM AUTHOR]

Only a few methods can be applied in a simple manner to estimate the genetic control of autoimmunity in humans. Here we examined the heritability of autoantibodies to two thyroid antigens; thyroglobulin (Tg) and thyroperoxidase (TPO, formerly known as thyroid microsomal antigen), using methods of regression of offspring on mid-parental values (ROMP). With the data sets available, affected and unaffected siblings were compared by this rapid screening method using results determined by hemagglutination (HA). The presence of both types of autoantibodies showed positive heritability in patients with Graves' thyrotoxicosis (TT), but it was not observed in chronic lymphocytic or Hashimoto's thyroiditis (CLT) patients. Since these assays have been extensively used over the years by most diagnostic and research laboratories, they should provide some insight as to which quantifiable parameters may be usefully accumulated to help select groups of patients and their families for further genetic study. ROMP may also be useful to determine the sequential appearance of different types of antibody in predicting disease onset in other family members, and in distinguishing maternal and paternal effects on imprinting. The method may be extended to study epitope spreading and other measures of disease progression. [ABSTRACT FROM AUTHOR]

Investigates natural killer cell (NKT) regulation of autoimmune thyroiditis. Association of NKT cells with the pathogenesis of thyroiditis; Characterization of NKT cells; Functions of NKT cells; Recognition by NKT cells; Microenvironment of cytokines.

Background: Pituitary antibodies have been reported with greater frequency in patients with Hashimoto's thyroiditis than in healthy controls, although there is significant variability in the strength of the association and the methodologies used. Methods: We designed a nested case-control study to characterize the prevalence of pituitary antibodies at the time of the clinical diagnosis of Hashimoto's thyroiditis, as well as at 2, 5, and 7 years before diagnosis. Active component female service member cases ( n=87) and matched female controls ( n=107) were selected using the Defense Medical Surveillance System database (DMSSD) between January 1998 and December 2007. Pituitary antibodies were measured by immunofluorescence using human pituitary glands collected at autopsy as the substrate. Results: At diagnosis, pituitary antibodies were present in 9% of cases with Hashimoto's (8 of 87) and 3% of controls (3 of 107). When the data were analyzed using a conditional logistic regression model, which takes into account the matching on age and work status, pituitary antibodies increased the odds of having Hashimoto's thyroiditis by sevenfold (95% confidence interval from 1.3 to 40.1, p=0.028), after adjusting for components of the DMSSD-category-termed race and for thyroperoxidase antibodies. Before diagnosis, pituitary antibodies were positive in 3 of the 11 subjects (2 cases and 1 control) at the −2-year time point, and negative in all 11 subjects at the −5- and −7-year time points. Conclusions: In summary, using a nested case-control design, we confirm that pituitary antibodies are more common in Hashimoto's thyroiditis and suggest that they appear late during its natural history. [ABSTRACT FROM AUTHOR]

Using a simple screening technique called regression of offspring on mid-parent (ROMP) to examine the role of IgG subclasses in affected and unaffected siblings of children and adolescents with autoimmune thyroid disease and their parents, both total-restricted and subclass-restricted autoantibodies to thyroglobulin (Tg) were assayed quantitatively for each of the IgG subclasses. There was a significant correlation of anti-Tg titer of probands with parental titers in thyrotoxicosis (TT), ( R2  ==  0.569, p  ==  0.001), but not in chronic lymphocytic thyroiditis. The most striking correlation was in TT patients of African-American ancestry, ( R2  ==  0.9863, p  ==  0.0007). Additional insight is provided by examining the contributions of the IgG subclasses individually, particularly those whose concentrations appear not to have direct influence on the total IgG titers. Thus, using small numbers of patients, and assaying the IgG subclass distributions, as well as any other immunoglobulin isotypes that are significantly altered in autoantibody assays, ROMP can be performed rapidly to ascertain which quantifiable parameters may be usefully extended to predict disease onset and progression. [ABSTRACT FROM AUTHOR]

To study the role of invariant Natural Killer T cell ( iNKT) cells in autoimmune thyroiditis, we derived two iNKT cell lines fromthe spleens of NOD· H2h4 mice, a strain that develops spontaneous autoimmune thyroiditis exacerbated by excess dietary iodine. The two lines were CD1d-restricted and expressed CD4+, DX5+, and theVα4Jα281 gene segment, of the T-cell receptor α locus. Upon stimulation with α-galactosyl-ceramide (α-GalCer), both lines rapidly produced IL-2, IL-4, IFN-γ, IL-10, and TNF-α. Strikingly, a similar cytokine response was also induced by thyroglobulin, one of the most abundant protein in the thyroid gland and a major autoantigen in human autoimmune thyroiditis. Transfer of the iNKT cell lines to syngeneic hosts enhanced autoimmune thyroiditis. Intraperitoneal injections of α-GalCer in iodine primed mice also induced thyroid disease. This paper reports for the first time that iNKT cells respond to thyroglobulin and enhance autoimmune thyroiditis in iodine fed NOD·H2h4 mice. [ABSTRACT FROM AUTHOR]

Abstract: Autoimmune diseases comprise a group of about 85 heterogeneous conditions that can affect virtually any organ and tissue in the body. Many autoimmune diseases change significantly during pregnancy: some ameliorate, some worsen, and others are unaffected. Two autoimmune diseases present prominently in relation to pregnancy: postpartum autoimmune thyroiditis and autoimmune hypophysitis. This article will review the current state of knowledge of the immunological changes that occur during normal pregnancy, and will explore the striking temporal association with pregnancy observed in thyroiditis and hypophysitis. [Copyright &y& Elsevier]